The influence of the time-of-day administration of the drug on the pharmacokinetics of sunitinib in rabbits

OBJECTIVES: At present it is known that the adjustment of the anticancer therapy to the circadian rhythms in tissues reduces the toxicity of the treatment. Chronotherapy also increases the efficacy of the anticancer treatment, which has been proved for many drugs. Sunitinib is a tyrosine kinase inhibitor, which is broadly used for the treatment of numerous cancers. The aim of the study was a comparison of the concentrations and pharmacokinetics of sunitinib after a single administration to rabbits at 08:00 (control group) and 20:00. Additionally, the effect of sunitinib on glucose levels was investigated. MATERIALS AND METHODS: The research was carried out on two groups of rabbits: I08:00, a group with the drug administered at 08:00 (n=8) and II20:00, a group with the drug administered at 20:00 (n=8). The rabbits were treated with sunitinib at an oral dose of 25 mg. Plasma concentrations of sunitinib and its metabolite (SU12662) were measured with a validated HPLC method with UV detection. RESULTS: The comparison of the sunitinib Cmax and AUC0-t in the group with sunitinib administered at 20:00 with the control group gave the ratios of 2.20 (90% confidence interval (CI) (2.17; 2.22) and 1.64 (1.61; 1.68), respectively. Statistically significant differences between the groups under analysis were revealed for Cmax (p \u3c 0.0001), AUC0-t (p = 0.0079), AUC0-∞ (p = 0.0149), and tmax (p = 0.0085). The mean glycemia drop was higher in group I08:00. than in group II20:00 (22.7% vs. 14.3%; p = 0.0622). The glycemia values returned to the initial values in 24 h after the administration of the drug in both groups. CONCLUSIONS: The research proved a significant influence of the time-of-day administration on the pharmacokinetics of sunitinib

The 42nd Symposium Chromatographic Methods of Investigating Organic Compounds : Book of abstracts

The 42nd Symposium Chromatographic Methods of Investigating Organic Compounds : Book of abstracts. June 4-7, 2019, Szczyrk, Polan

Affinity of Compounds for Phosphatydylcholine-Based Immobilized Artificial Membrane—A Measure of Their Bioconcentration in Aquatic Organisms

The BCF (bioconcentration factor) of solutes in aquatic organisms is an important parameter because many undesired chemicals enter the ecosystem and affect the wildlife. Chromatographic retention factor log kwIAM obtained from immobilized artificial membrane (IAM) HPLC chromatography with buffered, aqueous mobile phases and calculated molecular descriptors obtained for a group of 120 structurally unrelated compounds were used to generate useful models of log BCF. It was established that log kwIAM obtained in the conditions described in this study is not sufficient as a sole predictor of bioconcentration. Simple, potentially useful models based on log kwIAM and a selection of readily available, calculated descriptors and accounting for over 88% of total variability were generated using multiple linear regression (MLR), partial least squares (PLS) regression and artificial neural networks (ANN). The models proposed in the study were tested on an external group of 120 compounds and on a group of 40 compounds with known experimental log BCF values. It was established that a relatively simple MLR model containing four independent variables leads to satisfying BCF predictions and is more intuitive than PLS or ANN models

IAM Chromatographic Models of Skin Permeation

Chromatographic retention factor log kIAM obtained from IAM HPLC chromatography with buffered aqueous mobile phases and calculated molecular descriptors (surface area—Sa; molar volume—VM; polar surface area—PSA; count of freely rotable bonds—FRB; H-bond acceptor count—HA; energy of the highest occupied molecular orbital—EHOMO; energy of the lowest unoccupied orbital—ELUMO; and polarizability—α) obtained for a group of 160 structurally unrelated compounds were tested in order to generate useful models of solutes’ skin permeability coefficient log Kp. It was established that log kIAM obtained in the conditions described in this study is not sufficient as a sole predictor of the skin permeability coefficient. Simple put, potentially useful models based on log kIAM and readily available calculated descriptors, accounting for 85 to 91% of the total variability, were generated using Multiple Linear Regression (MLR).The models proposed in the study were tested on a group of 20 compounds with known experimental log Kp values

RP-18 HPLC Analysis of Drugs’ Ability to Cross the Blood-Brain Barrier

One hundred ten compounds of diverse structures (actives and excipients used in pharmaceutical preparations) were studied by RP-18 HPLC with acetonitrile-pH 7.4 phosphate buffer 1 : 1 (v/v) as the mobile phase. The relationships between the BBB permeation coefficients and the chromatographic parameters log k and (log k)/PSA were compared to those between the blood-brain barrier (BBB) permeation parameters and the RP-18 TLC descriptors Rf and Rf/PSA known from our earlier studies. It was found that the correlations between the BBB permeability and the HPLC data are slightly worse than those achieved for the thin-layer chromatographic data. MLR analysis based upon the physicochemical data confirmed the value of the molecular descriptors, related to the CNS bioavailability. These variables, combined with the HPLC data, made it possible to generate computational models, explaining 70–96% of the total variance of the CNS bioavailability. Contrary to TLC Rf, the advantage of the modification of HPLC log k with PSA (polar surface area) has not been confirmed and the results obtained with log k are superior to those obtained after a novel (log k)/PSA parameter has been introduced. Establishing a firm threshold limit of (log k)/PSA, log k, or even k and k/PSA to distinguish between the CNS+ and CNS− compounds was impossible. On the other hand, discriminant function analyses involving log k and (log k)/PSA as discriminating variables separated the CNS+ and CNS− compounds with the success rate ca. 90%. On the basis of these results, it was concluded that the RP-18 HPLC analytical models are entirely successful in studies and predictions of the BBB permeability

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

The Blood-Brain Barrier (BBB) permeability is an important factor governing a drug’s ability to act upon the Central Nervous System. The measure of the BBB permeability used throughout this study is the log BB (the blood/brain partitioning coefficient) measured in vivo or calculated. Useful yet simple models of the BBB permeability were developed by Stepwise Multiple Regression Analysis based on the chromatographic parameters Rf and Rf/PSA obtained by RP-18 TLC with acetonitrile - pH 7.4 phosphate buffered saline 70:30 (v/v) as mobile phase, combined with descriptors - the number of H-bond donors (HD), the number of H-bond acceptors (HA), energy of the highest occupied molecular orbital – (eH), energy of the lowest unoccupied molecular orbital (eL). The ability of the solutes to cross the BBB has been studied qualitatively using Discriminant Function Analysis. Almost all compounds with the known BB vivo parameter were correctly classified as CNS+/-. The classification functions based on Rf/PSA have been verified using an external group. The results of the chromatographic analysis proposed in this study (RP-18 TLC) are a source of valuable information on the BBB permeability of compounds available even on a very small scale

Quantification of Sunscreen Benzophenone-4 in Hair Shampoos by Hydrophilic Interactions Thin-Layer Chromatography/Densitometry or Derivative UV Spectrophotometry

Benzophenone-4 (BZ4) was separated from surfactants, dyes, preservatives, and other components of hair shampoos by thin-layer chromatography on silica gel 60 stationary phase, with ethyl acetate-ethanol-water-pH 6 phosphate buffer (15 : 7 : 5 : 1 v/v/v/v) as mobile phase. Densitometry scanning of chromatograms was performed at 285 nm. The densitometric calibration curve for BZ4 was nonlinear (second-degree polynomial), with R>0.999. The limits of detection and quantification were ca. 0.03 and ca. 0.1 μg spot−1, respectively. The results obtained by HPTLC-densitometry were compared to those obtained by zero and 2nd derivative UV spectrophotometry. In the case of spectrophotometric methods, calibration curves were linear with R>0.9998. The chromatographic method was fully validated

Quantification of synthetic food dyes in beverages or pharmaceutical tablets by solid phase extraction (spe) followed by UV/VIS spectrophotometry

Synthetic food dyes (E102, E104, E110, E122, E124, E132, E133) were concentrated by solid phase extraction on aminopropyl modified silica with aqueous sodium hydroxide or selected amines as eluents. Ponceau 4R (E124) was used as the model dye in the studies of the elution step. The recoveries of E124 differed depending on the eluent and ranged from 76% (AMP) to over 90% (TEA, imidazole, NaOH). Diluted aqueous triethanolamine (TEA) was found to be a suitable eluent for E124 but other dyes were eluted more effectively with NaOH. The solid extraction process was combined with UV/VIS spectroscopy to quantify synthetic dyes in drinks and OTC pharmaceutical tablets. The SPE-UV/VIS spectroscopic method was validated in terms of linearity, accuracy (recovery of dyes from spiked preparations), precision (repeatability, intermediate precision) and limits of detection/quantification. The method was found sufficiently fast, easy and reliable for the routine control of dyes in these types of products

The influence of the time-of-day administration of the drug on the pharmacokinetics of sunitinib in rabbits

OBJECTIVES: At present it is known that the adjustment of the anticancer therapy to the circadian rhythms in tissues reduces the toxicity of the treatment. Chronotherapy also increases the efficacy of the anticancer treatment, which has been proved for many drugs. Sunitinib is a tyrosine kinase inhibitor, which is broadly used for the treatment of numerous cancers. The aim of the study was a comparison of the concentrations and pharmacokinetics of sunitinib after a single administration to rabbits at 08:00 (control group) and 20:00. Additionally, the effect of sunitinib on glucose levels was investigated. MATERIALS AND METHODS: The research was carried out on two groups of rabbits: I08:00, a group with the drug administered at 08:00 (n=8) and II20:00, a group with the drug administered at 20:00 (n=8). The rabbits were treated with sunitinib at an oral dose of 25 mg. Plasma concentrations of sunitinib and its metabolite (SU12662) were measured with a validated HPLC method with UV detection. RESULTS: The comparison of the sunitinib Cmax and AUC0-t in the group with sunitinib administered at 20:00 with the control group gave the ratios of 2.20 (90% confidence interval (CI) (2.17; 2.22) and 1.64 (1.61; 1.68), respectively. Statistically significant differences between the groups under analysis were revealed for Cmax (p CONCLUSIONS: The research proved a significant influence of the time-of-day administration on the pharmacokinetics of sunitinib.This article is published as Szałek, E., A. Karbownik, K. Sobańska, W. Połom, T. Grabowski, A. Wolc, M. Matuszewski, and E. Grześkowiak. "The influence of the time-of-day administration of the drug on the pharmacokinetics of sunitinib in rabbits." Eur Rev Med Pharmacol Sci 18, no. 16 (2014): 2393-2399.</p

The Rise of Three Rs Centres and Platforms in Europe.

Public awareness and discussion about animal experiments and replacement methods has greatly increased in recent years. The term 'the Three Rs', which stands for the Replacement, Reduction and Refinement of animal experiments, is inseparably linked in this context. A common goal within the Three Rs scientific community is to develop predictive non-animal models and to better integrate all available data from in vitro, in silico and omics technologies into regulatory decision-making processes regarding, for example, the toxicity of chemicals, drugs or food ingredients. In addition, it is a general concern to implement (human) non-animal methods in basic research. Toward these efforts, there has been an ever-increasing number of Three Rs centres and platforms established over recent years - not only to develop novel methods, but also to disseminate knowledge and help to implement the Three Rs principles in policies and education. The adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes gave a strong impetus to the creation of Three Rs initiatives, in the form of centres and platforms. As the first of a series of papers, this article gives an overview of the European Three Rs centres and platforms, and their historical development. The subsequent articles, to be published over the course of ATLA's 50th Anniversary year, will summarise the current focus and tasks as well as the future and the plans of the Three Rs centres and platforms. The Three Rs centres and platforms are very important points of contact and play an immense role in their respective countries as 'on the ground' facilitators of Directive 2010/63/EU. They are also invaluable for the widespread dissemination of information and for promoting implementation of the Three Rs in general